Proteins are essential constituents of all known living organisms, whose specific functions are determined by their unique three-dimensional structure (the so-called native structure). This structure is, in turn, determined by the amino-acid sequence. A reliable method for the prediction of three-dimensional structure from sequence would allow both for the prediction of the structures of newly discovered proteins, and estimation of the effect of mutations on structure and, thereby, function of enzymes, signaling proteins, neurotransmitters, etc., which are directly related to the origin of cancer and genetically-caused diseases. According to the thermodynamic hypothesis of Anfinsen, the native conformation of a protein is a global-energy minimum on its free- energy hypersurface. The search for the global-minimum energy of a polypeptide chain in an all-atom representation is still limited to chains composed of up to 30 amino-acid residues, while the size of typical small proteins is greater than 50 amino-acid residues. Therefore, simplified united-residue models of polypeptide chains, in which each amino-acid residue is represented by one or a few interaction sites, have received much attention, because, in contrast to the all- atom representation they are simple enough for carrying out large-scale conformational searches ill real time. In most of the united-residue approaches applied nowadays, the polypeptide chain is superposed on a discrete lattice. Although such an approach greatly simplifies the evaluation of the conformational energy, it prevents the use of efficient methods for smoothing the energy surface, such as the Diffusion-Equation method or the Distance-Scaling Method. The current proposal aims at the implementation of these global-optimization techniques to an off-lattice united-residue force field that is under development in our groups. The ability to search the conformational space efficiently will, in turn, enable us to refine the parameters of the force field so that it can locate the native structure as definitely lowest in energy, with respect to possible misfolded structures. it can be expected that such an approach will provide a useful tool for d novo prediction of the structures of globular proteins.